Treatment of pd-l1 positive lung cancer using an anti-pd-1 antibody

Abstract

This disclosure provides a method for treating a subject afflicted with a PD-L1 positive non-squamous non-small cell lung cancer (NSCLC). The method comprises administering to the subject a therapeutically effective amount of an anti-PD-1 anti-body or anti-PD-L1 antibody. In some embodiments, the non-squamous NSCLC tumor has a PD-L1 expression of at least about 1%. In some embodiments, the subject is additionally administered another anti-cancer agent.

What is claimed is: 
     
         1 . A method for treating a subject afflicted with a tumor derived from a non-squamous non-small cell lung cancer (NSCLC) comprising administering to the subject a therapeutically effective amount of:
 an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 receptor (PD-1) or Programmed Death-Ligand 1 (PD-L1) and inhibits PD-1 activity (“anti-PD-1 antibody”) or PD-L1 activity (“anti-PD-L1 antibody”), respectively,   wherein the tumor has a PD-L1 expression of at least about 1%.   
     
     
         2 . A method of treating a subject afflicted with a tumor derived from a non-squamous NSCLC comprising:
 (i) measuring a PD-L1 expression on the tumor, wherein the tumor has a PD-L1 expression of at least about 1% and   (ii) administering to the subject a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding portion thereof or an anti-PD-L1 antibody or antigen-binding portion thereof.   
     
     
         3 . A method for identifying a subject afflicted with a tumor derived from a non-squamous NSCLC who is suitable for an anti-PD-1 antibody or anti-PD-L1 antibody therapy comprising measuring a PD-L1 expression on the tumor, wherein the tumor has a PD-L1 expression of at least about 1% and wherein the subject is administered a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding portion thereof or an anti-PD-L1 antibody or antigen-binding portion thereof. 
     
     
         4 . A method for identifying a subject afflicted with a tumor derived from a non-squamous NSCLC who is suitable for an anti-PD-1 antibody or anti-PD-L1 antibody therapy comprising:
 (i) measuring a PD-L1 expression on the tumor, wherein the tumor has a PD-L1 expression of at least about 1% and   (ii) administering to the subject a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding portion thereof or an anti-PD-L1 antibody or antigen-binding portion thereof.   
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the PD-L1 expression of the tumor is at least about 5%. 
     
     
         6 . The method of any one of  claims 1 - 4 , wherein the PD-L1 expression of the tumor is at least about 10%. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1. 
     
     
         8 . The method of any one of  claims 1 - 7 , wherein the anti-PD-1 antibody or antigen-binding portion thereof is a chimeric, humanized or human monoclonal antibody or a portion thereof. 
     
     
         9 . The method of any one of  claims 1 - 8 , wherein the anti-PD-1 antibody or antigen-binding portion thereof comprises a heavy chain constant region which is of a human IgG1 or IgG4 isotype. 
     
     
         10 . The method of any one of  claims 1 - 9 , wherein the anti-PD-1 antibody is nivolumab. 
     
     
         11 . The method of any one of  claims 1 - 9 , wherein the anti-PD-1 antibody is pembrolizumab. 
     
     
         12 . The method of any one of  claim 1 - 6 , wherein the anti-PD-L1 antibody or antigen-binding fragment thereof competes for binding with BMS-936559, MPDL3280A, MEDI4736 or MSB0010718C for binding to human PD-L1. 
     
     
         13 . The method of any one of  claims 1 - 6  and  12 , wherein the anti-PD-L1 antibody or antigen-binding portion thereof is a chimeric, humanized or human monoclonal antibody or a portion thereof. 
     
     
         14 . The method of any one of  claims 1 - 6  and  12 - 13 , wherein the anti-PD-L1 antibody or antigen-binding portion thereof comprises a heavy chain constant region which is of a human IgG1 or IgG4 isotype. 
     
     
         15 . The method of any one of  claims 1 - 6  and  12 - 14 , wherein the anti-PD-L1 antibody is BMS-936559. 
     
     
         16 . The method of any one of  claims 1 - 6  and  12 - 14 , wherein the anti-PD-L1 antibody is MPDL3280A. 
     
     
         17 . The method of any one of  claims 1 - 6  and  12 - 14 , wherein the anti-PD-L1 antibody is MEDI4736. 
     
     
         18 . The method of any one of  claims 1 - 6  and  12 - 14 , wherein the anti-PD-L1 antibody is MSB0010718C. 
     
     
         19 . The method of any one of  claims 1 - 18 , wherein the anti-PD-1 antibody or antigen-binding portion thereof or the anti-PD-L1 antibody or antigen-binding portion thereof is administered at a dose ranging from at least about 0.1 to at least about 10.0 mg/kg body weight once every about 2, about 3 or about 4 weeks. 
     
     
         20 . The method of  claim 19 , wherein the anti-PD-1 antibody or antigen-binding portion thereof or the anti-PD-L1 antibody or antigen-binding portion thereof is administered at a dose of at least about 3 mg/kg body weight once about every 2 weeks. 
     
     
         21 . The method of any of  claims 1 - 20 , wherein the anti-PD-1 antibody or antigen-binding portion or the anti-PD-L1 antibody or antigen-binding portion thereof is administered for as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs. 
     
     
         22 . The method of any one of  claims 1 - 21 , wherein the tumor has a PD-L1 expression that is at least about 5%. 
     
     
         23 . The method of any one of  claims 1 - 22 , wherein the tumor has a PD-L1 expression that is at least about 10%. 
     
     
         24 . The method of any one of  claims 1 - 24 , wherein the subject has had prior treatment with platinum-based doublet chemotherapy (PT-DC). 
     
     
         25 . The method of any one of  claims 1 - 25 , wherein the subject exhibits an overall survival of at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after the administration. 
     
     
         26 . The method of  claim 25 , wherein the tumor has a PD-L1 expression of at least about 1% and the subject exhibits the overall survival of at least about 17 months. 
     
     
         27 . The method of  claim 25 , wherein the tumor has a PD-L1 expression of at least about 5% and the subject exhibits the overall survival of at least about 18 months. 
     
     
         28 . The method of  claim 25 , wherein the tumor has a PD-L1 expression of at least about 10% and the subject exhibits the overall survival of at least about 19 months. 
     
     
         29 . The method of any one of  claims 1 - 28 , wherein the subject has an overall response rate of at least about 30%, 35%, 36%, 37%, 39%, 40%, 45%, or 50% after the administration compared to the response rate after administration of Docetaxel. 
     
     
         30 . The method of  claim 29 , wherein the tumor has a PD-L1 expression of at least about 1% and the subject exhibits an overall response rate of at least about 31%. 
     
     
         31 . The method of  claim 29 , wherein the tumor has a PD-L1 expression of at least about 5% and the subject exhibits an overall response rate of at least about 35%. 
     
     
         32 . The method of  claim 29 , wherein the tumor has a PD-L1 expression of at least about 10% and the subject exhibits an overall response rate of at least about 37%. 
     
     
         33 . The method of any one of  claims 1 - 32 , wherein the subject exhibits a median duration of response of at least about 16 months. 
     
     
         34 . The method of any one of  claims 1 - 33 , wherein the anti-PD-1 antibody or portion thereof or the anti-PD-L1 antibody or portion thereof is formulated for intravenous administration. 
     
     
         35 . The method of any one of  claims 1 - 34 , wherein the anti-PD-1 antibody or antigen-binding portion thereof or the anti-PD-L1 antibody or antigen-binding portion thereof is administered at a subtherapeutic dose. 
     
     
         36 . The method of any one of  claims 1  to  35 , which further comprising administering one or more additional anti-cancer agent. 
     
     
         37 . The method of  claim 36 , wherein the anti-cancer agent is selected from the group consisting of an antibody or antigen-binding portion thereof that binds specifically to a CTLA-4 and inhibits CTLA-4 activity, a chemotherapy, a platinum-based doublet chemotherapy, a tyrosine kinase inhibitor, or an anti-VEGF inhibitor. 
     
     
         38 . The method of  claim 36 , wherein the anti-cancer agent is an antibody or antigen-binding portion thereof that binds specifically to a CTLA-4 and inhibits CTLA-4 activity. 
     
     
         39 . The method of any one of  claims 1  to  38 , wherein the PD-L1 expression is measured by automated immunohistochemistry (IHC). 
     
     
         40 . A kit for treating a subject afflicted with a tumor derived from a non-squamous NSCLC, the kit comprising:
 (a) an anti-PD-1 antibody or antigen-binding portion thereof or an anti-PD-L1 antibody or antigen-binding portion thereof;   (b) instructions for determining the PD-L1 expression of the tumor and, if the tumor expresses PD-L1, administering the anti-PD-1 antibody or antigen-binding portion thereof or an anti-PD-L1 antibody or antigen-binding portion thereof to the subject in the methods of  claims 1 - 39 .   
     
     
         41 . The kit of  claim 40 , further comprising an agent to determine the PD-L1 expression of the tumor. 
     
     
         42 . The kit of  claim 41 , wherein the PD-L1 expression is measured by an anti-PD-L1 antibody or antigen-binding portion thereof.